Spatial Extent and Heterogeneity of Water at Phospholipid Membranes Revealed by Molecular Dynamics

Water at phospholipid membrane interfaces critically influences membrane stability, permeability, and biomolecular interactions, yet the spatial extent and nature of membrane-induced perturbations remain incompletely characterized. Here we review atomistic molecular dynamics simulations of dimyristoylphosphatidylcholine (DMPC) bilayers across varying hydration levels to elucidate water behavior at the membrane interface. The results reveal that while water dynamics recover bulk-like behavior approximately 1.2 nm from the membrane, structural anomalies persist up to ~2.5 nm, indicating a decoupling of structural and dynamical properties. We identify distinct populations of inner, bound, and unbound water with heterogeneous structural and dynamical characteristics; bound water forms stable hydrogen bonds with lipids and exhibits markedly slowed dynamics, whereas unbound water progressively attains bulk-like behavior. Bound and unbound water form an interface marked by a sudden change in their properties: bound water, as well as inner water, is structurally and dynamically membrane-like, while unbound water is bulk-like. These findings refine the concept of hydration water and have important implications for understanding membrane functionality, biomolecular interactions, and improving computational models of biological systems.